Structure based virtual screening, molecular dynamic simulation to identify the oxadiazole derivatives as inhibitors of Enterococcus D-Ala-D-Ser ligase for combating vancomycin resistance

Vancomycin resistance in enterococci mainly arises due to alteration in terminal peptidoglycan dipeptide. A comprehensive structural analysis for substrate specificity of dipeptide modifying d-Alanine: d-Serine ligase (Ddls) is essential to screen its inhibitors for combating vancomycin resistance. In this study modeled 3D structure of EgDdls from E. gallinarum was used for structure based virtual screening (SBVS) of oxadiazole derivatives. Initially, fifteen oxadiazole derivatives were identified as inhibitors at the active site of EgDdls from PubChem database. Further, four EgDdls inhibitors were evaluated using pharmacokinetic profile and molecular docking. The results of molecular docking showed that oxadiazole inhibitors could bind preferentially at ATP binding pocket with the lowest binding energy. Further, molecular dynamics simulation results showed stable behavior of EgDdls in complex with screened inhibitors. The residues Phe172, Lys174, Glu217, Phe292, and Asn302 of EgDdls were mainly involved in interactions with screened inhibitors. Furthermore, MM-PBSA calculation showed electrostatic and van der Waals interactions mainly contribute to overall binding energy. The PCA analysis showed motion of central domain and omega loop of EgDdls. This is involved in the formation of native dipeptide and stabilized after binding of 2-(1-(Ethylsulfonyl) piperidin-4-yl)-5-(furan-2-yl)-1,3,4-oxadiazole, which could be reason for the inhibition of EgDdls. Hence, in this study we have screened inhibitors of EgDdls which could be useful to alleviate the vancomycin resistance problem in enterococci, involved in hospital-acquired infections, especially urinary tract infections (UTI). [Display omitted] •D-Ala-D-Ser ligase causes peptidoglycan dipeptide modification in VRE.•Molecular docking studies have revealed that Ddls of E. gallinarum form D-Ala-D-Ser instead of D-Ala-D-Ala.•Over 8976 compounds were screened for pharmacokinetic profiles, and SBVS revealed four EgDdls oxadiazole inhibitors.•Molecular docking and MD simulation results showed that four oxadiazole inhibitors bind at ATP binding pocket of EgDdls.•The PCA studies revealed the stability of central domain and omega loop, which could responsible for EgDdls inhibition.